New proteasome inhibitors in the treatment of multiple myeloma

Abstract The treatment of patients with relapsed and/or refractory multiple myeloma has improved considerably in the last 15 years, after the introduction of proteasome inhibitors and immunomodulatory drugs. The first clinical trials with new proteasome inhibitors have produced exciting results, particularly those comparing triplet regimens with standard doublet regimens, with a gain in progression-free survival accompanied by an acceptable safety profile and either similar or better health-related quality of life. New proteasome inhibitors hold the potential to fill unmet needs in multiple myeloma management regarding improvement of clinical outcomes, including delayed progression of disease in high-risk patients. This review summarizes the main pharmacological properties and clinical outcomes of these agents, and discusses their potential to change the whole multiple myeloma therapeutic landscape.

New proteasome inhibitors in the treatment of multiple myeloma.

The treatment of patients with relapsed and/or refractory multiple myeloma has improved considerably in the last 15 years, after the introduction of proteasome inhibitors and immunomodulatory drugs. The first clinical trials with new proteasome inhibitors have produced exciting results, particularly those comparing triplet regimens with standard doublet regimens, with a gain in progression-free survival accompanied by an acceptable safety profile and either similar or better health-related quality of life. New proteasome inhibitors hold the potential to fill unmet needs in multiple myeloma management regarding improvement of clinical outcomes, including delayed progression of disease in high-risk patients. This review summarizes the main pharmacological properties and clinical outcomes of these agents, and discusses their potential to change the whole multiple myeloma therapeutic landscape.

Unmet needs in multiple myeloma in Brazil from physicians' perspective ­ barriers in quality of life and disease management / Necessidades não atendidas em mieloma múltiplo no Brasil sob a perspectiva de médicos ­ barreiras na qualidade de vida e manejo da doença

Objective: There is an increasing trend of the overall survival rates of multiple myeloma (MM) patients over the years, increasing the necessity to improve their quality of life and attenuate unmet medical needs. Therefore, this study aims to explore and describe unmet medical needs and barriers in Brazilian MM patients, based on physicians' perspective. Methods: A questionnaire with 41 questions was developed to collect information regarding clinical characteristics, unmet medical needs and barriers for the diagnosis and treatment of MM in Brazil. After physicians' responses, a panel discussion with all the participants was had in order to collect additional data and validate physicians' responses. Results: Participants had a mean of 18 years of professional experience and attended to mean of thirty MM patients per month. MM patients treated by these physicians had a median time of disease of 7.5 months when initiating treatment in the public sector, and 2.5 months in the private sector. In both systems, the majority of patients referred were from general practitioners. Peripheral neuropathy was the most common adverse event reported with higher impact on patients' adherence and QoL. Conclusion: There are several challenges as to unmet medical needs, especially when comparing the private and public healthcare systems in Brazil. According to physicians, providing access to basic diagnostic procedures and adopting educational measures for both physicians and patients would help to minimize barriers in the current scenario of MM management in Brazil.

Objetivo: Existe uma tendência no aumento das taxas de sobrevida global de pacientes de mieloma múltiplo (MM) ao longo dos anos, aumentando a necessidade de melhorar sua qualidade de vida e atenuar as necessidades médicas não atendidas na área. Desta forma, o objetivo deste estudo explorar e descrever as necessidades médicas não atendidas e as barreiras em pacientes brasileiros de MM, a partir da perspectiva de médicos. Métodos: Um questionário com 41 questões foi desenvolvido para coletar dados sobre as características clínicas, necessidades médicas não atendidas e barreiras no diagnóstico e tratamento de MM no Brasil. Depois de coletar a resposta dos médicos, uma discussão em forma de painel com todos os participantes foi realizada para coletar dados adicionais validar as respostas do questionário. Resultados: Os participantes tinham, em média, 18 anos de experiência profissional, atendendo-se no total uma média de 30 pacientes de MM por mês. Os pacientes de MM atendidos por esses médicos no sistema público apresentam em média 7,5 meses de doença ao iniciar o tratamento, enquanto no sistema privado apresentavam 2,5 meses. Em ambos os sistemas, a maioria dos pacientes foi referenciada por clínicos gerais. Neuropatia periférica foi o evento adverso mais frequentemente reportado pelos médicos, com maior impacto na adesão ao tratamento e na qualidade de vida. Conclusão: Existem diversos desafios relativos às necessidades médicas não atendidas, especialmente ao comparar os sistemas público e privado no Brasil. De acordo com os participantes, o acesso aos procedimentos diagnósticos básicos e a adoção de medidas de educação médica e de pacientes minimizariam as barreiras importantes no cenário brasileiro atual.

Epstein-Barr Viral Load is Associated to Response in AIDS-Related Lymphomas.

AIDS-related lymphoma (ARL) development is associated to immunodeficiency state with proliferation of B-cells driven by HIV itself and EBV infection. However, Epstein-Barr DNA is not detected in malignant cells of all ARL subtypes. A prospective and controlled study to analyze EBV viral load (VL) in plasma and peripheral blood mononuclear cells (PBMC) of ARL patients was performed to analyze if Epstein-Barr VL could be related to response in these patients. Fifteen patients with ARL were included in this study with measurement of EBV VL at three different periods of time: at lymphoma diagnosis, upon completion of chemotherapy, and 3 months after. Two control groups composed by HIV-negative and HIV-positive patients were also evaluated for EBV VL comparison. In situ hybridization for EBER was performed on diagnostic samples of all ARL patients. Median EBV VL in PBMC and plasma had a significant decrease (p = 0.022 and p = 0.003, respectively) after ARL treatment. EBER was positive in 7 (46.7 %) cases. Median EBV VL in PBMC before lymphoma treatment in patients positive for EBER was significantly higher compared to EBER negative cases (p = 0.041). Reduction of EBV viral load during treatment of lymphoma could be predictive of response. EBER expression was associated to advanced stages of disease and worse immune status. Our study suggests that measurement of EBV VL during ARL treatment could be used as a marker for response, but further studies are needed to validate this association.

Assessment of labile plasma iron in patients who undergo hematopoietic stem cell transplantation.

Body iron disorders have been reported after myeloablative conditioning in patients undergoing hematopoietic stem cell transplantation (HSCT). There is a concern that labile plasma iron (LPI), the redox-active form of iron, can be involved in the occurrence of toxicity and other complications commonly observed in the early post-HSCT period. In order to better understand the LPI kinetics and its determinants and implications, we undertook sequential LPI determinations before and after conditioning until engraftment in 25 auto-HSCT patients. Increased LPI was present in only 5 patients before starting conditioning. Shortly after conditioning, LPI levels were increased in 23 patients, with peak at day 0, returning to normal range upon engraftment in 21 patients. Overall, LPI levels correlated weakly with serum ferritin and more strongly with transferrin saturation; however, both parameters were apparently not applicable as surrogate markers for increased LPI. Although this was a small cohort, logistic regression suggested that baseline LPI levels could predict occurrence of grade III or IV toxicity. In conclusion, LPI kinetics is influenced by aplasia following conditioning and engraftment. Measuring LPI before starting conditioning can offer an opportunity to predict toxicity and, perhaps, the need for chelation therapy.

FOXP3(+) regulatory and TIA-1(+) cytotoxic T lymphocytes in HIV-associated Hodgkin lymphoma.

Human immunodeficiency virus (HIV) infects CD4(+) lymphocytes, leading to a development of malignant lymphomas, such as HIV-associated Hodgkin Lymphoma (HIV-HL). This study aimed to assess the differences in cellular composition of the inflammatory reactive background of HIV-HLs. We examined infiltrating T lymphocytes, specifically regulatory T cells, cytotoxic cells, Epstein-Barr virus (EBV) related antigens and HIV-receptor CCR5. In all HIV-HL cases, Hodgkin and Reed-Sternberg (HRS) cells showed EBER1 expression, LMP-1 staining positivity and EBNA-2 staining negativity, except for one case which showed LMP-1 staining negativity. Our histological findings indicate the percentage of CD8(+) , TIA-1(+) lymphocytes was significantly higher in HIV-HL than in non-HIV-HL cases (P < 0.05). On the other hand, the percentage of CD4(+) , FOXP3(+) lymphocytes was significantly lower in HIV-HL than in non-HIV-HL cases (P < 0.05) but present. The percentage of CCR5(+) lymphocytes was significantly lower in HIV-HL than in non-HIV-HL cases (P < 0.05). Usually, CD4(+) and CCR5(+) lymphocytes are reported to be rarely detected in HIV-associated non-Hodgkin lymphomas, but the presence of CD4(+) and/or FOXP3(+) lymphocytes may be implicated in the pathogenesis of HL. In addition, although additional CD8(+) lymphocytes are probably not EBV-LMP specific cytotoxic T-cells, these lymphocytes may also well be involved in the pathogenesis of HIV-HL.

Thrombocytopenia in HIV-Infected Patients.

Thrombocytopenia is a common feature among HIV-positive patients. However, there are few reports about this subject after highly active antiretroviral therapy (HAART) introduction. The authors show a retrospective description of epidemiology, clinical aspects, and treatment observed in 55 HIV-positive outpatients with thrombocytopenia treated in two reference centers for HIV treatment in São Paulo, Brazil. Thirty-four (62%) patients were male, 50 (91%) were Caucasian, with median of lymphocytes TCD4 of 394 cells/mm(3). In 63.6% patients, the cause of thrombocytopenia was classified as immune thrombocytopenic purpura and non immune in 25.5%. Regular use of HAART was present in 43.6% of the population studied. In 20% HAART was initiated for thrombocytopenia treatment with improvement in platelets count observed after 3 months. Platelet transfusion was needed in 23.7% of the patients and one patient died due to bleeding. Thrombocytopenia is still common among patients infected with HIV, considered a multifactor disorder, commonly due to immune mechanisms in our cases. In the clinical setting, a diagnostic approach related to the hematological consequences of HIV infection is needed for a better therapy option for this population.

Detecção do vírus de Epstein-Barr (EBV), expressão de FOXP3 e avaliação da carga viral para EBV como marcadores prognósticos nos linfomas relacionados à AIDS / Epstein-Barr virus (EBV) detection, FOXP3 expression and evaluation of EBV viral load as prognostic markers in Aids-related lymphomas

Introdução: Pacientes com infecção pelo HIV têm risco aumentado para o desenvolvimento de linfomas não-Hodgkin de células B comparado à população geral. Dentre os mecanismos que podem estar relacionados a esta patologia, encontra-se a reativação do vírus de Epstein-Barr secundária a imunossupressão. O papel do sistema imune para desenvolvimento de tumores é citado há longa data, e seu equilíbrio é mantido pelos linfócitos T regulatórios, cujo principal regulador e marcador é o fator de transcrição FOXP3. Neste estudo, avaliamos a presença de EBER e FOXP3 em amostras diagnósticas, além da carga viral para o vírus de Epstein-Barr em pacientes com linfomas relacionados à Aids a fim de avaliar e correlacionar os resultados como marcadores prognósticos nesta população. Métodos: Análise prospectiva da carga viral para Epstein-Barr no plasma e em células mononucleares do sangue periférico em 15 pacientes com linfomas relacionados à Aids acompanhados no Serviço de Hematologia do Instituto de Infectologia Emílio Ribas e do Hospital das Clínicas/Instituto do Câncer do Estado de São Paulo da Faculdade de Medicina da Universidade de São Paulo. As mensurações foram realizadas para cada paciente por reação da cadeia de polimerase em tempo real ao diagnóstico, término do tratamento e três meses após o término do tratamento. Dois grupos controles constituídos de 26 pacientes infectados pelo HIV em uso de anti-retroviral e sem diagnóstico de linfoma ou infecção oportunista e 30 indivíduos saudáveis também foram analisados para comparação da carga viral para o vírus de Epstein-Barr. Amostras coletadas por biópsia para o diagnóstico de linfoma foram submetidas a análise imuno-histoquímica para FOXP3 e para EBER por hibridização in situ. Resultados: 13 pacientes eram do sexo masculino e dois do sexo feminino, dos quais 14 foram tratados com quimioterapia e um com radioterapia de sistema nervoso central. Nove de 15 pacientes (60%) completaram o tratamento proposto...

Introduction: Patients with HIV infection have increased risk for development of non-Hodgkins lymphoma compared to general population. Among mechanisms that could be related to this disease is the reactivation of Epstein-Barr virus infection secondary to immunosuppression. The role of immune system in development of tumors was reported a long time ago, and balance of this system is maintained by regulatory T cells; FOXP3 transcription factor is the main regulator and marker of these cells. In this study we evaluated the presence of EBER and FOXP3 in diagnostic samples, and also viral load of Epstein-Barr virus in patients with Aids-related lymphoma to evaluate and correlate the results as prognostic markers in this population. Methods: Prospective analysis of viral load of Epstein-Barr virus in plasma and peripheral blood mononuclear cells from 15 patients with Aids-related lymphoma treated at Instituto de Infectologia Emílio Ribas and Hospital das Clínicas/Instituto do Câncer do Estado de São Paulo da Faculdade de Medicina da Universidade de São Paulo. Viral load measures were performed by real time polymerase chain reaction at diagnosis of lymphoma, completion of treatment and three months afterwards. Two control groups composed by 26 HIV-positive patients in use of HAART and without diagnosis of lymphoma or opportunistic infection and 30 healthy persons were also analyzed for viral load comparison. Biopsy samples performed to lymphoma diagnosis were submitted to immunohistochemistry for FOXP3 and in situ hybridization to EBER. Results: 13 patients were male and two females, 14 were treated with chemotherapy and one with radiotherapy of central nervous system. Nine of 15 patients (60%) completed treatment achieving complete remission. Median viral load of Epstein-Barr virus before treatment was 13 copies/106 in peripheral blood mononuclear cells (1-1472 copies/106) and 70 copies/mL (0-24900 copies/mL) in plasma. After treatment it was 0,5/106 (0-109,5)...

A prognostic score for AIDS-related diffuse large B-cell lymphoma in Brazil.

The aim of this study was to evaluate a prognostic score for aids-related lymphoma (ARL). A retrospective study of 104 patients with ARL treated between January 1999 and December 2007 was conducted. Diffuse large B-cell lymphoma (DLBC) was the most observed histological type (79.8%). The median CD4 lymphocyte count at lymphoma diagnosis was 125 cells per microliter. Treatment response could be evaluated in 83 (79.8%) patients, and 38 (45.8%) reached complete remission (CR); overall response rate was 51.8% (95 CI = 38.5-65.1%). After a median follow-up of 48 months, the 4-year overall survival (OS) rate among all patients was 35.8%, with a median survival time of 9.7 months (95% CI = 5.5-13.9 months). The survival risk factors observed in multivariate analysis (previous AIDS and high-intermediate/high international prognostic index (IPI)) were combined to construct a risk score, which divided the whole patient population in three distinct groups as low, intermediate, and high risk. When this score was applied to DLBC patients, a clear distinction in response rates and in OS could be demonstrated. Median disease-free survival (DFS) for patients that achieved CR was not reached, and DFS in 4 years was 83.0%. Our results show that the reduced OS observed could be explained by poor immune status with advanced stage of disease seen in our population of HIV-positive patients. Further studies will be needed to clarify the role of different treatment approaches for ARL in the setting of marked immunosuppression and to identify a group of patients to whom intensive therapy could be performed with a curative intent.

Primary effusion lymphoma with cardiac involvement in HIV positive patient-complete response and long survival with chemotherapy and HAART.

Primary effusion lymphoma (PEL) is a rare type of lymphoma related to herpesvirus-8 (HHV-8), and considered an AIDS-defining condition. The authors describe a case of PEL with cardiac involvement occurring in an HIV-positive patient treated with HAART and chemotherapy, who achieved complete remission and long survival.

Hodgkin lymphoma among patients infected with HIV in post-HAART era.

BACKGROUND: Hodgkin lymphoma is considered a common type of non-AIDS defining tumor among patients infected with HIV, commonly presenting as a widespread disease and with different pathologic features compared with Hodgkin lymphoma in the general population. Despite that, the best treatment option is undefined. PATIENTS AND METHODS: The authors present a retrospective study of 31 patients with Hodgkin lymphoma-HIV attended at 3 Brazilian centers, 2 of them considered reference centers for HIV treatment. Chemotherapy schemes used were ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) or hybrid MOPP-ABV (mechlorethamine/vincristine/procarbazine/prednisone-doxorubicin/bleomycin/vinblastine), with prophylactic granulocyte colony-stimulating factor. RESULTS: Treatment response could be evaluated in 22 patients (70.9%) who completed initial treatment: 20 (91%) reached complete remission, 1 had partial remission, and 1 did not exhibit a response. The overall response rate was 95.5% (95% confidence interval, 91.2%-99.8%). After a median follow-up of 3 years, the overall survival (OS) rate among all patients was 80.3%; median OS was not reached. On univariate analysis, only CD4 cell count at diagnosis was significantly related to survival. CONCLUSION: This retrospective study shows that for patients with Hodgkin lymphoma development in the HIV setting in these 3 Brazilian centers, there was high complete remission and satisfactory OS rates, comparable with results found for Hodgkin lymphoma in patients without HIV.

Bone marrow biopsy in the diagnoses of infectious and non-infectious causes in patients with advanced HIV infection.

AIMS: Fever and peripheral blood abnormalities in patients with advanced acquired immunodeficiency syndrome are usually due to disseminated opportunistic infections. The objective of this study was to evaluate the diagnostic yield of histopathological and microbiological investigations of bone marrow samples from HIV-infected patients with fever and/or cytopenias. METHODS AND RESULTS: The diagnostic utility of bone marrow aspiration, biopsy and culture was retrospectively examined in 82 patients with HIV/AIDS (median CD4 count 51 microL(-1), range 1-430 microL(-1)) with peripheral cytopenias and/or fever attended at a large tertiary care hospital in Brazil during a one-year period. The diagnostic yield of bone marrow biopsy was 34.1% (28 cases) in contrast to only 8.5% (eight cases) attained by the bone marrow smear. Opportunistic pathogens were isolated from bone marrow cultures in 26.8% of patients. CONCLUSIONS: Bone marrow biopsy has value in diagnosis of opportunistic infections, malignancies or other conditions in one-third of adult patients with advanced AIDS and fever or cytopenias and should be considered in this patient group.

P-glycoprotein expression in non-Hodgkin's lymphomas of human immunodeficiency virus infected patients.

Multidrug resistance (MDR) is a challenge in cancer treatment. One of the most studied mechanisms is P-glycoprotein (P-gp), which acts as a drug efflux pump, with decreased intracellular accumulation of drugs. It still needs to be clarified whether P-gp expression has a significant impact on non-Hodgkin's lymphoma treatment response, but a poor outcome has been reported in patients with positive P-gp expression. AIDS-related lymphomas have aggressive behavior, and although a complete response could be achieved, relapse is not uncommon. In an attempt to determine a possible relationship between MDR and poor outcome in this population, histologic samples obtained from 45 non-Hodgkin's lymphoma HIV-infected patients without previous cytotoxic therapy were submitted to immunohistochemical analysis using monoclonal antibody C494 specific for the MDR-1 isoform of P-gp. Samples from 27 patients (60%) were positive. Response to treatment (P=0.02) and overall survival (P=0.001) were significantly lower in patients with positive P-gp expression. In patients having achieved complete remission, the median disease-free survival (DFS) was not reached; the mean DFS was 57.2 months with DFS rates of 72.9% in three years. Our results show that P-gp is expressed before treatment of non-Hodgkin's lymphoma of HIV patients, and is related to poor response to treatment and overall survival.

Non-Hodgkin's lymphoma among patients infected with human immunodeficiency virus: the experience of a single center in Brazil.

The relative risk of non-Hodgkin's lymphoma (NHL) among patients infected with human immunodeficiency virus (HIV) is elevated compared with the general population. We describe a retrospective study of 78 HIV-infected patients with NHL treated between 1999 and 2006 at the Infectology Institute, a reference center for HIV treatment in São Paulo, Brazil. All patients were treated with standard CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone). An evaluation of treatment response was available for 48 (61.5%) of the patients who completed initial treatment. Twenty-three patients (47.9%) achieved a complete response (CR), 3 (6.3%) achieved a partial response, and 22 (45.8%) failed to respond to treatment. Of the 30 patients (38.5%) who were not available for response evaluation, 23 died of sepsis during treatment, 5 abandoned treatment, and 2 are still under treatment. After a median follow-up of 3 years, the overall survival rate for all patients is 20.5%. A univariate analysis showed a significant CR rate in patients with respect to the following factors: no acquired immunodeficiency syndrome (AIDS) diagnosis prior to the lymphoma, disease stage of I to II, and an International Prognostic Index (IPI) of low or low-intermediate risk. A multivariate analysis indicated that only a previous AIDS diagnosis and the IPI were significantly related to the CR rate. A median disease-free survival (DFS) time for the patients who achieved a CR was not reached, with a mean survival time of 73 months and a 3-year DFS rate of 77.5%. Our results provide additional information regarding HIV-related lymphoma in Brazil.

Bone marrow pathology in AIDS.

Bone marrow morphology is frequently abnormal in patients with AIDS. In this study, we reviewed 97 bone marrow biopsies of AIDS patients performed between 1998 and 2000 in the Emílio Ribas Institute of Infectology, which is the reference department for HIV. Specific diagnoses were performed in 33 cases. Fungi were observed in eight cases. Five of them were Histoplasma capsulatum, two were Cryptococcus neoformans, and one probably Candida albicans. Acid-fast bacilli were observed in 12 bone marrow biopsies, three of which were diagnosed to have no mycobacteriosis clinically. Foci of necrosis with clusters of macrophages without any well-formed granuloma were observed in nine cases and well-formed granuloma in three cases. Lymphomatous infiltration was observed in four cases of non-Hodgkin's lymphoma and in two Hodgkin's diseases (mixed cellularity). Extensive necrosis of bone marrow was observed in one case of Burkitt's lymphoma. In conclusion, bone marrow biopsy should be performed to elucidate the etiology of cytopenias, secondary infections, and fever of undetermined origin in AIDS patients.